1. Field of the Invention
This invention relates to methods and compositions for treating male impotence and erectile dysfunction.
2. Description of the Prior Art
The process of erection is generally a selective vasodilation of the spongy penile tissue and corpus cavernosum and reductions in outflow, leading to blood pooling, elevation of intra-cavernous pressure, and therefore erection.
Conventional therapies for impotence or erectile dysfunction primarily include local administration of vascular smooth muscle relaxants, for example papaverine or prostaglandin E1, or .alpha.-adrenoceptor antagonists, such a phentolamine, resulting in penile erection because of an increase in arterial inflow of blood, distension of sinusoids and possible restriction of venous outflow. Thus, intracavernous injection of vasoactive drugs offers impotent patients a form of therapeutic management, and allows one of the tests for differential diagnosis between vasculogenic and other etiologic forms of impotence. Papaverine and prostaglandin E1 are also used in the assessment of pharmacological response of penile erectile tissues under experimental conditions (see Chen et al., J. Urol., 147:1124-1128, 1992).
Other pharmaceutical treatments for impotence have been practiced in the prior art. These include systemic administration of male hormonal preparations such as methyltestosterone and testosterone esters, as well as administration of various naturally occurring plant extracts believed to have aphrodisiac properties, such as yohimbine, ginseng, strychnine and the like. Non-pharmacological therapeutic modalities for impotence include the surgical implantation of penile prostheses and the use of tourniquet-like devices which fit tightly around the shaft of the penis and restrict the flow of blood through the surface veins and the deeper dorsal vein to prolong erection.
All of the foregoing prior art treatment methods suffer from obvious and serious disadvantages. The injection of papaverine and other vasoactive drugs meets with variable success and variable duration of response, and repeated injections into the penis can be painful and traumatic. In some patients these agents cause priapism (undesirable sustained erection), which can lead to structural damage to the organ. The administration of methyltestosterone or testosterone esters may cause toxic effects or inhibit endogenous testosterone formation and spermatogenesis. Orally administered aphrodisiac substances are of marginal and erratic efficacy, and some have significant adverse side effects. The use of surgical implants or tourniquet-like devices can lead to serious problems of infection and trauma, and cause discomfort to both male and female partners.
Several recent studies have shown the obligatory role of nitric oxide for the erection process (see for example Rajfer et al., N. Eng. J. Med., 326:90-94, 1992). Stimulation of the local nerve leads to production of NO and vasorelaxation, leading to erection. Because of the importance of NO in erection, NO donors may have utility for the treatment of impotence. Hence, it has recently been proposed to use nitric oxide donors such as nitroglycerin (see U.S. Pat. No. 5,059,603) and linsidomine chlorhydrate (see Urology, 44:553-556, 1994) applied topically or via intracavernosal injection to treat impotence and erectile dysfunction.
The use of these and other nitric oxide donors proposed in the literature for treatment of impotence is also less than completely satisfactory. Nitroglycerin, even when applied topically as an ointment, has received variable responses and may cause severe headaches (see Talley et al., Ann. Int. Med., 103:804, 1985). Of even greater concern is that systemic absorption of most vasoactive agents causes significant reductions in systemic blood pressure resulting in side effects such as light-headedness, increased heart rate, etc., and sometimes causing activation of the sympathetic nervous system leading directly to de-tumescence. For these reasons, the use of nitroglycerin for the treatment of impotence is less than ideal.
Improved pharmaceutical compositions and methods are required for treatment of impotence while avoiding the serious adverse effects experienced with prior art treatment modalities.